Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease. Clinically, it is characterized by progressive deficits in memory and other cognitive functions that occur in the face of an otherwise normal neurological examination. Postmortem examination reveals a variety of typical AD brain lesions, including deposition of amyloid plaques, formation of neurofibrillary tangles, and neuronal degeneration.
The amyloid deposits characteristic of AD pathology consist of aggregates of a 39-42 amino acid peptide termed .beta./A4 (G. G. Glenner and C. W. Wong, Biochem. Biophys. Res. Comm., 120: 885 (1984); C. L. Masters, et al., Proc. Natl. Acad. Sci. USA, 82: 4245 (1985); D. J. Selkoe, et al., J. Neurochem., 46: 1820 (1986)), which is an abnormal cleavage product of a larger amyloid precursor protein (APP) (J. membrane glycoprotein, existing as several distinct forms derived from alternative mRNA splicing (R. E. Tanzi, et al., Nature, 331: 528-530 (1988); P. Ponte, et al., Nature, 331: 525 (1988); N. Kitaguchi, et al., Nature., 331: 530 (1988)). Water-soluble APP fragments lacking the COOH terminus (APP.sup.s) have been detected in conditioned cell culture media and in human cerebrospinal fluid (A. Weidemann, et al., Cell,57: 115, (1989), M. R. Palmert, et al., Proc. Natl. Acad. Sci. USA, 86: 6338 (1989)), indicating that APP.sup.s is a secretory protein. Normal secretion of water-soluble NH.sub.2 -terminal APP fragments involves cleavage of full-length APP at an extracellular site located close to the transmembrane domain, and within the .beta./A4 domain (T. Oltersdorf, et al., Nature, 341: 144 (1989); F. S. Esch, et al., Science, 248: 1122 (1990); S.S. Sisodia, et al., Science, 248: 492 (1990); J. P. Anderson, et al., Neurosci. Lett., 128: 126 (1991); R. Wang, et al., J. Biol. Chem., 262: 16960 (1991)). This cleavage event presumably precludes the formation of amyloidogenic APP fragments. It is also possible that APP is processed by an internal lysosomal pathway (C. Haass, A. Y. Hung, D. J. Selkoe, J. Neurosci., 11: 3783 (1991); C. Haass, E. H. Koo, A. Mellon, A. Y. Hung, D. J. Selkoe, Nature, 356: 500 (1992)) that may generate amyloidogenic cleavage products (S. Estus, et al., Science, 255: 726 (1992); T. E. Golde, S. Estus, L. H. Younkin, D. J. Selkoe, S. G. Younkin, Science, 255: 728 (1992)). It is therefore likely that aberrations of APP processing pathways contribute to amyloid formation. The mechanisms regulating cellular APP processing, however, are unknown.